BACKGROUND: We investigated myocardial protection by human atrial natriuretic peptide (hANP) during cardiac surgery without cardioplegia and determined whether suppression of myocardial ischemic reperfusion injury by hANP allows intraoperative aortic cross-clamp time to be prolonged. METHODS AND RESULTS: Thirty-two pigs were placed on cardiopulmonary bypass. Experimental pigs were divided into 4 groups: 15min clamping; hANP 15min clamping; 30min clamping; and hANP 30min clamping. In both hANP groups, a 100μg dose of hANP was administered after clamping. Left ventricular function, premature ventricular contractions (PVCs), histopathological studies, 8-isoprostane, myocardial Ca(2+), and ATP concentrations were determined. Comparison of the myocardial contractile force indicator E(max), in the 30min groups, showed a significantly higher recovery rate in the hANP than in the control group. PVC numbers were significantly lower in the hANP than in the control groups for both arrest durations. On microscopic examination, hANP reduced ischemic reperfusion injury in the 30min groups. The myocardial ATP level was significantly higher in the hANP 30min than in the control 30min group. Increases in 8-isoprostane and myocardial Ca(2+) concentrations were significantly inhibited in both hANP groups. CONCLUSIONS: This study demonstrated that hANP ameliorates ischemic reperfusion injury, improves postoperative myocardial contractility, and reduces reperfusion arrhythmias. We suggest that hANP allows aortic cross-clamping to be prolonged and thereby exerts a direct myocardial protective effect against cardiac arrest during cardiac surgery.